The NIH's molecular library program has been instigated to provide ready public-domain access to small molecules of potential utility as probes for biological processes or as the starting points for potential therapeutics. In order to sustain growth in this program new and novel libraries of small molecules are needed. This proposal aims to provide molecules that are closely related to previously identified 'high-value' structures and that fall into two classes: libraries that are based around small molecule drugs and libraries that are based around the structural motifs found in natural products with biological activity. Specifically, the proposed molecules include heterocycles that are close relatives to kinase inhibitors, structures based on tetrahydroisoquinolines and homologs, polycyclic ethers, simple pyrans, and compounds that are suggested to be orthologs of complex polycyclic natural products. PUBLIC HEALTH RELEVANCE: Small molecules, whether they be based on natural products or purely synthetic foundations, are widely considered to be the most valuable of agents to understand and treat human disease. This work focuses on the production of complex structures that can be assembled in a handful of steps as part of a pipeline of molecules that may lead to the discovery of new biology and that ultimately may have potential to impact on a variety of diseases.